Semicarbazide sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1) and encoded by the human AOC3 gene, belongs to a family of copper-containing amine oxidases and is a human endothelial cell adhesion molecule with a dual function. On the one hand it has a unique and restricted expression pattern mediating lymphocyte binding to vascular endothelium. The level of SSAO/VAP-1 is upregulated in the vasculature at the sites of inflammation, specifically on the surface of vascular endothelia cells mediating leukocyte entry to inflammatory sites.
On the other hand SSAO/VAP-1 exhibits monoamine oxidase (MAO) activity which is present in the extracellular domain of the protein. SSAO/VAP-1 is distinguished from the widely distributed mitochondrial MAO-A and MAO-B flavoproteins with respect to amino acid sequence, 2,4,5-trihydroxyphenylalanyl quinone (TPQ) cofactor, biological function, substrates, and subcellular distribution.
SSAO/VAP-1 located on the vascular endothelial cell surface catalyzes the oxidative deamination of primary aliphatic and aromatic monoamines with the following reaction pathway.RNH2+O2+H2O→RCHO+H2O2+NH3 
The enzymatic reaction of the amine results in the formation of a corresponding aldehyde, H2O2, and ammonia, which generally are more cytotoxic than the substrates themselves. Products of SSAO/VAP-1 such as formaldehyde are mainly extracellular. The potential toxic effects of formaldehyde towards blood vessels may be amplified by the absence of formaldehyde dehydrogenase from the blood plasma, where SSAO/VAP-1 products are formed.
The physiological substrates of SSAO/VAP-1 in man have not been clearly identified, although methylamine and aminoacetone have been shown to be good substrates for SSAO/VAP-1. Methylamine is a product of various human biochemical pathways for the degradation of creatine, sarcosine, and adrenaline, and is found in various mammalian tissues and in blood. It can also be derived from the diet by gut bacterial degradation of dietary precursors or ingested in food and cigarette smoke. The concentration of methylamine in the blood can be increased in certain physiological and pathological situations such as diabetes.
SSAO/VAP-1 exists as a membrane-bound and a soluble form, which is present in the plasma, and its activity shows wide tissue distribution. The major sources of the enzyme are the endothelial cells, smooth muscle cells, and adipocytes. Since expression of SSAO/VAP-1 is especially remarkable in vascular smooth muscle, endothelium and plasma, cytotoxic effects associated with it may be pronounced in highly vascularised tissues, such as the kidneys and the retina. The amount of soluble SSAO/VAP-1 is elevated in both Type I and Type II diabetes and the increased level of toxic aldehydes and oxygen radicals in the local environment of the endothelial cell produced by the oxidative amination of these substrates could damage the vascular cells leading to vascular damage, which may explain late stage diabetic complications found in these patients. Increased levels of methylamine and aminoacetone have been reported in patients with Type I or Type II diabetes and it has been proposed that the vasculopathies such as retinopathy, neuropathy, and nephropathy and atherosclerosis seen in late stage diabetes could be treated with specific inhibitors of SSAO/VAP-1 activity.
The pathway of leukocyte adhesion to endothelial cells has been proposed to be directly involved with the SSAO/VAP-1 activity by a novel mechanism involving direct interaction with an amine substrate presented on a SSAO/VAP-1 ligand expressed on the surface of a leukocyte. Therefore inhibitors of SSAO/VAP-1 activity could be expected to reduce leukocyte adhesion in areas of inflammation by reducing leukocyte trafficking into the inflamed area and therefore the inflammatory process itself.
Additionally, in human clinical tissue samples the expression of SSAO/VAP-1 is induced at the sites of inflammation. This increased level of SSAO/VAP-1 can further lead to increased production of H2O2 by the oxidative deamination pathway. H2O2 is a known signalling molecule upregulating other adhesion molecules. This increased adhesion molecule expression may further lead to enhance leukocyte trafficking into areas where SSAO/VAP-1 is expressed. Thus inhibitors of the enzymatic activity of SSAO/VAP may serve as anti-inflammatory agents.
SSAO/VAP-1 has been proposed as a potential target for the treatment of obesity due to the observation that its expression is induced during adipogenesis. A role for SSAP/VAP-1 in apoptosis has also been proposed. In healthy humans the plasma activity of SSAO/VAP-1 is rather constant. Elevated SSAO/VAP-1 levels or over-expression of the enzyme have been observed in several pathological conditions and diseases including congestive heart failure, end-stage renal disease, multiple sclerosis, psoriasis, Alzheimer's disease, and myopathies and diabetes, inflammatory liver diseases and liver fibrosis.
Due to the proposed involvement of SSAO/VAP-1 in a number of inflammatory processes and various pathologies, inhibitors of SSAO/VAP-1 that can have therapeutic value in the prevention or the treatment of such disorders or diseases are in great demand. Several small-molecule inhibitors of SSAO/VAP-1 have been identified, including hydrazine derivatives, phenylallylhydrazines (WO2006/094201, WO2005/014530), hydrazine alcohols and hydrazine indanes (WO2002/0202090, WO2003/006003, WO2005/08319), arylalkylamines, propenyl- and propargylamines, oxazolidinones, haloalkylamines, 1,3,4-oxadiazines (WO2002/0202541), 4,5,6,7-tetrahydroimidazo-[4,5-c]pyridines (WO2002/0238153, WO2010/031789), pyrazolo[4,3-c]pyridines (WO2010/031791), imidazopyridines (WO2010/064020), thiazole derivates (WO2004/087138, WO2004/067521, WO2004/067521, WO2006/028269, WO2006/011631), haloallylamines (WO2009/066152), compounds having an oxime moiety (WO2010/09373), and compounds disclosed in WO2005/082343.
Compounds for medicinal use comprising a pyridazinone or pyridinone moiety have been disclosed, including pirfenidone analogs and derivatives (WO2010/135470, US2009/0318455, US2010/0190731) and MEK inhibitors (US2005/0250782).
Known from CAPlus-database and available from commercial sources is 5-phenoxy-2-phenyl-6-(1H-1,2,4-triazol-3-yl)pyridazin-3(2H)-one which falls under the definition of the present invention. However, no field of use or identification data is given for this molecule.